Tubocurarine muscle-relaxant activity

C-Toxiferine possesses 250 times stronger muscle relaxant activity than D-tubocurarine, described in Section 1.5. However, it has drawbacks, in that it is too long acting to control muscle relaxant activity accurately, and it is also unstable in solution. 

Full understanding is hampered by current deficiencies in our knowledge of the chemical composition of the plants concerned—for tubocurarine has so far only been found in Chondrodendron tomentosum—yet, as demonstrated by the curare formulas given in Section 1.2.3.1, there are curares from regions 2 and 3 that do not have this species as an ingredient, so that their muscle-relaxant activity must be due to alkaloids from other plants, e.g. Abuta (cf. Section 1.4.6.4) or Cur area species. 

It is one of the ironies of the curare story that a large part of the work leading to the development of synthetic analogues with improved muscle-relaxant properties has been based on two myths (a) the belief that (+)-tubocurarine was a bis-quaternary alkaloid, and (b) the belief that an inter-onium distance, i.e. the distance between the two hetero-atoms (nitrogen), of about 10 carbon atoms was optimal for muscle-relaxant activity. More recent developments have shown that neither condition is essential vecuronium is a monoquaternary compound and atracurium has 13 atoms between its two quaternary nitrogen atoms (536). But, however that may be, it is the active principles from curares that have provided both insight and some of the models which lie at the basis of these newer and improved muscle relaxants. 

Bisbenzylisoquinoline alkaloids are dimeric benzyltetrahydroisoquinoline alkaloids that are known for their pharmacological activities. A well-described example is the muscle relaxant (+)-tubocurarine, which in crude form serves as an arrow poison for South American Indian tribes. In the biosynthesis of this broad class of dimeric alkaloids, it has been postulated that the mechanism of phenol coupling proceeds by generation of phenolate radicals followed by radical pairing to form either an inter- or intramolecular C - O or C - C bond. Enzyme studies on the formation of bisbenzylisoquinoline alkaloids indicated that a cytochrome P-450-dependent oxidase catalyzes C - O bound formation in the biosynthesis of berbamunine in Berberis cell suspension culture.15 This enzyme, berbamunine synthase (CYP80A1), is one of the few cytochromes P-450 that can be purified to... 

Another interesting alkaloid is tubocurarine chloride (14), with a bisbenzyliso-quinoline structure. It is the active principle of tubocurare, an arrow poison used by Indians in South America and medicinally used as a muscle relaxant. However, the source, the leaves of the tropical rainwood liane Chondodenron tomento-sum, is not easily accessible and the compound exhibits unwanted side-effects. Investigations showed that the basic structure can be replaced by an appropriate steroid skeleton with two nitrogen substituents at the right distance (see next section). 

Tubocurarine acts as a competitive inhibitor in the nicotinic acetylcholine receptor, meaning that the nerve impulse is blocked by this alkaloid. Tubocurarine is used in surgical practice as a muscle relaxant. These alkaloids have an observably large spectrum of activity and possible applications. Their utilization in the development of new applications is therefore relatively active in modern medicine. 

In the mice head-drop test for curare-like activity compounds 210, 212 and 213 were found to be very potent. In analogy to d-tubocurarine, decamethonium and other muscle relaxants, these compounds cause a neuromuscular block when administered intraperitoneally. 

Bisbenzylisoquinolines (macrocyclic or linear, formed by 2 benzylisoquinolines) (+)-tubocurarine (macrocyclic) (acetylcholine (nicotinic) receptor antagonist and skeletal muscle relaxant major component of Chondrodendron species (Menispermaceae) pareira bark-derived curare arrow poison) dauricine (linear) (Menispermaceae curarelike anaesthetic) rodiasine (macrocyclic) (Ocotoea venenosa (Lauraceae) curare-like skeletal muscle relaxant) cepharanthine (macrocyclic) (Stephania species (Menispermaceae) anti-mycobacterial active against leprosy and tuberculosis). 

Plant extract used by South American Indians to prepare poison arrows. Sold with different names (e.g. Tube-curare) depending on the container used for packaging. Toxicologically active principle is the alkaloid tubocurarine chloride. Muscle relaxant, toxic by respiratory paralysis and hypotension competitive blocker ACh receptor in muscle. 

It exerts a weak and feeble neuromuscular blocking activity which fails to produce signifieant muscle relaxation except imder deep ether anaesthesia. It has been found to potentiate the neuromuscular blockade caused by tubocurarine and to antagonize the action of decamethonium. Paradoxically, it has been used successfully to prolong and potentiate the relaxant effects of suxamethonium chloride. Besides, it has also been reported to decrease suxamethonium-induced muscular fasciculations. 

The principle is fairly plain, even an old one. In 1939, the active ingredient of curare—an ancient plant toxin weapon still in use by Indians—was isolated for the first time. In 1943, it was introduced successfully into anesthesiology. Curare provided adequate muscle relaxation without the depressant effect of deep anesthesia induced by ether or chloroform. Over the last 20 years, physicians have used curare to ease the stiffened muscles caused by polio and to treat such diverse conditions as lockjaw, epilepsy, and cholea (a nervous disorder characterized by uncontrollable muscle movements). Eventually, more effective treatments were found for these illnesses, but the active ingredient of curare, d-tubocurarine, led to the skeletal muscle relaxant Intocostrin, which has been used in surgery ever since. Synthetic analogs of d-tubocurarine are used tens of thousands of times per day in the operating room [309]. 

Tubocurarine causes muscle relaxation by blocking nerve receptors at the motor muscle by competitive binding to the acetyl choline receptor. This mode of action is generally described in the field of pharmacology as the curarizing activity. 

It is (H-)-tubocurarine and its associated alkaloids that have been at the centre of interest. The monoquaternary (H-)-tubocurarine (18j) is rather less active than the parent bis-quaternary indole bases. The head-drop dose in the mouse is about 125 fig/kg and in man about 150 /tg/kg (252). In contrast, the enantiomeric (—)-tubocurarine (181) is 30-60 times weaker (354). (H-)-Chondrocurarine (18n), the fully N-methylated alkaloid and the base with the bis-quaternary structure originally assigned to (+)-tubocurarine, has almost four times the potency of that alkaloid. It is responsible for a considerable part of the activity of Chondrodendron tomentosum extracts (353). Data supposedly for 0,0 -dimethyl-(+)-tubocurarine (18m) are probably for the completely methylated AT,0,0 -trimethyl derivative (18o), since the method used for its preparation also quaternizes the tertiary nitrogen (500). The compound is two to three times more potent than (H-)-tubocurarine it is also known as metocurine and has acquired limited use in surgery as a muscle relaxant (501). The muscle-relaxant properties of quaternized curine derivatives continue to be investigated (see 345 and references cited therein). 

Curare and its active principles belong to the first of the two groups indicated above. Thus, toxiferine, (-h)-tubocurarine, and related compounds are competitive or nondepolarizing muscle relaxants, i.e. they compete with acetylcholine for the recognition sites on the receptor channels. These sites... 

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